Zvi Fuks, MD

In this lab

Studies from this laboratory have provided evidence that in addition to DNA damage, ionizing radiation can act upon cellular membranes to initiate apoptotic death. Specifically, it has been demonstrated that acid sphingomyelinase (ASMase)-mediated ceramide generation signals radiation-induced apoptosis. Although supported by biochemical, cellbiological, and genetic data, the prevalence of this apoptotic mechanism remains unknown. The purpose of current studies is to establish the biochemical regulation of ceramide generation in response to radiation, and the tissues in which this response prevails. New model systems and reagents have been developed to study the tissue distribution of this response and the potential for its modulation by pharmacologic intervention. These pathophysiologic studies may have direct relevance to human disease with immediate potential for clinical translation.

Endothelial cells appear particularly sensitive to ASMase-mediated apoptosis in vitro and in vivo. Disruption of the ASMasegene but not the p53 gene inhibits microvascular endothelial apoptosis in a variety of irradiated tissues, and treatment with basic fibroblastgrowth factor (bFGF) produces a similar anti-apoptotic effect via inhibition of ASMase.

Further, microvascular endothelial apoptosis constitutes a primary and critical event in the pathogenesis of radiation damage to several normal tissues, including the small intestines, lungs, and the central nervous system. Blocking endothelial apoptosis pharmacologically by intravenous bFGF or genetically by ASMasedeletion, prevented the evolution of tissue damage, organ failure, and death from radiation enteritis or pneumonitis. These tissue responses in rodents serve as readout systems in pharmacologic approaches to modulate the level of radiation-induced ceramide and its pro-apoptotic function, and in the design of signaling-based apoptosis therapy for tumors and tissues that use ceramide as mediator of radiation damage.

In addition to the investigations described above, we have a prgram on the role of DNA damage-induced apoptosis. Our data strongly support the concept that DNA damage activates the enzyme ceramide synthase via the de novo synthesis of the sphingolipid and ceramide within the mitochondria. Ceramide synthase activation is negatively regulated by the Ataxia Telangiectasia-Mutated (ATM) gene. In human prostate cell lines LNCaP and CRW22Rv1, which are radioresistant, TPA (phorbol ester) reduces ATM levels and serves as a radiosensitizer. These are new and heretofore unknown mechanisms that could provide a basis for modulating the radiation response in resistant human prostate tumor clones. Targeted disruption of ATM in prostate cancer cells might lead to radiation-induced apoptosis via ceramide synthase signaling. Further identification of molecular targets within this pathway and development of specific reagents or small molecules aimed at ATM inactivation would appear warranted in the treatment of prostate cancer.

Zvi Fuks has been elected a member of the Institute of Medicine. The Institute of Medicine (IOM) is a branch of the National Academies and was established to honor professional achievement in the health sciences and to serve as a national resource for recommendations on issues related to medicine, biomedical sciences, and health. Membership in the IOM is considered one of the highest honors in the fields of health and medicine.

acid (A-sid)

A chemical that gives off hydrogen ions in water and forms salts by combining with certain metals. Acids have a sour taste and turn certain dyes red. Some acids made by the body, such as gastric acid, can help organs work the way they should. An example of an acid is hydrochloric acid. Acidity is measured on a scale called the pH scale. On this scale, a value of 7 is neutral, and a pH value of less than 7 to 0 shows increasing acidity.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

apoptosis (A-pop-TOH-sis)

A type of cell death in which a series of molecular steps in a cell leads to its death. This is the body’s normal way of getting rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

ataxia (uh-TAK-see-uh)

Loss of muscle coordination.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

biological (BY-oh-LAH-jih-kul)

Pertaining to biology or to life and living things. In medicine, refers to a substance made from a living organism or its products. Biologicals may be used to prevent, diagnose, treat or relieve of symptoms of a disease. For example, antibodies, interleukins, and vaccines are biologicals. Biological also refers to parents and children who are related by blood.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cancer (KAN-ser)

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cell (sel)

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

central nervous system (SEN-trul NER-vus SIS-tem)

The brain and spinal cord. Also called CNS.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

ceramide (SAYR-uh-mide)

A type of lipid (fat) found in the membranes of cells and the covers of nerves. Some ceramides are important in signal transduction (the process by which a cell responds to substances in its environment) and may cause some types of cells to die. Ceramides are being studied in the treatment of cancer.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

clinical (KLIH-nih-kul)

Having to do with the examination and treatment of patients.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

deletion

Absence of a segment of DNA; may be as small as a single base or as large as a whole chromosome.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

DNA

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

enzyme (EN-zime)

A protein that speeds up chemical reactions in the body.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

fibroblast (FY-broh-blast)

A connective tissue cell that makes and secretes collagen proteins.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

gene (jeen)

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetic (jeh-NEH-tik)

Inherited; having to do with information that is passed from parents to offspring through genes in sperm and egg cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

growth factor (grothe FAK-ter)

A substance made by the body that functions to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

intervention (IN-ter-VEN-shun)

In medicine, a treatment or action taken to prevent or treat disease, or improve health in other ways.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

intravenous (IN-truh-VEE-nus)

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called IV.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

ionizing radiation (I-uh-NY-zing RAY-dee-AY-shun)

A type of radiation made (or given off ) by x-ray procedures, radioactive substances, rays that enter the Earth's atmosphere from outer space, and other sources. At high doses, ionizing radiation increases chemical activity inside cells and can lead to health risks, including cancer.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

irradiated (ih-RAY-dee-AY-ted)

Treated with radiation.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

medicine (MEH-dih-sin)

Refers to the practices and procedures used for the prevention, treatment, or relief of symptoms of a diseases or abnormal conditions. This term may also refer to a legal drug used for the same purpose.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

mitochondria (MY-toh-KON-dree-uh)

Small structures in a cell that are found in the cytoplasm (fluid that surrounds the cell nucleus). Mitochondria make most of the energy for the cell and have their own genetic material that is different from the genetic material found in the nucleus. Many diseases are caused by mutations (changes) in the DNA of mitochondria. Mitochondria are cell organelles.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

modulate (MAH-juh-layt)

To adjust, or change.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

organ (OR-gun)

A part of the body that performs a specific function. For example, the heart is an organ.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

pneumonitis (NOO-moh-NY-tis)

Inflammation of the lungs. This may be caused by disease, infection, radiation therapy, allergy, or irritation of lung tissue by inhaled substances.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

prostate (PROS-tayt)

A gland in the male reproductive system. The prostate surrounds the part of the urethra (the tube that empties the bladder) just below the bladder, and produces a fluid that forms part of the semen.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

prostate cancer (PROS-tayt KAN-ser)

Cancer that forms in tissues of the prostate (a gland in the male reproductive system found below the bladder and in front of the rectum). Prostate cancer usually occurs in older men.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiation (RAY-dee-AY-shun)

Energy released in the form of particle or electromagnetic waves. Common sources of radiation include radon gas, cosmic rays from outer space, medical x-rays, and energy given off by a radioisotope (unstable form of a chemical element that releases radiation as it breaks down and becomes more stable).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiation enteritis (RAY-dee-AY-shun EN-teh-RY-tis)

Inflammation of the small intestine caused by radiation therapy to the abdomen, pelvis, or rectum. Symptoms include nausea, vomiting, abdominal pain and cramping, frequent bowel movements, watery or bloody diarrhea, fatty stools, and weight loss. Some of these symptoms may continue for a long time.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiosensitizer (RAY-dee-oh-SEN-sih-TY-zer)

A drug that makes tumor cells more sensitive to radiation therapy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

resistance

Failure of a cancer to shrink after treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

response (reh-SPONTS)

In medicine, an improvement related to treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

therapy (THAYR-uh-pee)

Treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tissue (TIH-shoo)

A group or layer of cells that work together to perform a specific function.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

TPA

A substance being studied in the treatment of leukemias and lymphomas. It is also being studied in the treatment of other types of cancer. TPA affects many cell actions and may cause tumor cells to die. It is a type of phorbol ester. Also called 12-O-tetradecanoylphorbol-13-acetate and tetradecanoylphorbol acetate.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

translation (trans-LAY-shun)

In biology, the process by which a cell makes proteins using the genetic information carried in messenger RNA (mRNA). The mRNA is made by copying DNA, and the information it carries tells the cell how to link amino acids together to form proteins.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tumor (TOO-mer)

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)